Is CIROP p.Arg389Ile (c.1166G>T) pathogenic?

CIROP p.Arg389Ile (c.1166G>T) is classified Pathogenic in CIROP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-03-15). AlphaMissense: likely pathogenic (0.7735); Absent from gnomAD v4.1; Associated with heterotaxy, visceral, 12, autosomal.

What condition is associated with CIROP p.Arg389Ile (c.1166G>T)?

CIROP p.Arg389Ile (c.1166G>T) is associated with heterotaxy, visceral, 12, autosomal (ClinVar).

How common is CIROP p.Arg389Ile (c.1166G>T) in the general population?

CIROP p.Arg389Ile (c.1166G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CIROP p.Arg389Ile (c.1166G>T)?

AlphaMissense predicts likely pathogenic (score 0.7735) — an in-silico prediction, not a clinical call.

CIROP p.Arg389Ile

c.1166G>T · rs2140282332 · VCV1344493

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7735 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Conditions

heterotaxy, visceral, 12, autosomal

Computational evidence

Protein change
AlphaMissense	0.7735	likely pathogenic ✓ concordant with ClinVar · top 9% in CIROP
SaProt	LLR -13.23	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2, phastCons 1
Regional constraint	o/e 1.77	unconstrained · MANE · 5,635 bp · p 1.3e-32 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CIROP
Protein: p.Arg389Ile
Coding: c.1166G>T
MANE Select: NM_001354640
dbSNP: rs2140282332
Type: single nucleotide variant
Location: chr14:23102235 (GRCh38)
Structure: AlphaFold pLDDT 73.73
Residue 389: a UniProt-annotated variant site (in htx12); a UniProt-annotated variant site (in htx12; uncertain significance)

Full CIROP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

heterotaxy, visceral, 12, autosomal — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIROP p.Gln528Ter Likely pathogenic ★ same condition
CIROP p.Arg22Ter Conflicting classifications of pathogenicity ★ same condition
CIROP p.Gly180Arg Uncertain significance ★ ⚠ same condition
CIROP p.Gly511Glu Uncertain significance ★ ⚠ same condition
CIROP p.Ser31Phe Conflicting classifications of pathogenicity ★ ⚠ same condition
CIROP p.Tyr68Cys Uncertain significance ★ ⚠ same condition
CIROP p.Arg191Ter Pathogenic same condition
CIROP p.Ser384Leu Pathogenic same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cirop-p-arg389ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown